FOXS1 promotes prostate cancer progression through the Hedgehog/Gli1 pathway

Prostate cancer (PCa) remains the most common malignant tumor in men, and the clinical treatment still faces many challenges. Several molecular biomarkers of PCa progression have been reported, however, whether FOXS1 can serve as a new biomarker in PCa remains unknown.FOXS1 and Gli1 expression was assessed by RT-qPCR and western blot. The binding and regulation roles between FOXS1 and Gli1 were confirmed by Co-IP and ubiquitination assays. Cell viability, proliferation, apoptosis, migration, invasion and EMT progress were assessed through CCK-8, colony formation, flow cytometry, wound-healing, transwell and western blot assays, respectively. In vivo nude mice tumorigenesis model was also conducted to verify PCa growth.FOXS1 was upregulated in the PCa TCGA dataset and cells. High FOXS1 level was correlated with PCa patients' worse tumor stage and shorter survival. FOXS1 knockdown inhibited PCa cell proliferation, invasion, migration, EMT and tumor growth while increased cell apoptosis. Furthermore, FOXS1 knockdown decreased the inactivation of Hedgehog (Hh) pathway. FOXS1 bind to Gli1 and decreased the ubiquitination of Gli1, which resulted in the upregulation of Gli1. Besides, both Gil1 overexpression and Hh signal activation reversed the suppression function of FOXS1 silencing on PCa growth and metastasis.FOXS1 bind and stabilized Gli1 by blocking Gli1 ubiquitination, thereby activating Hh signaling to promote PCa cell growth and metastasis.